|A new technology for encapsulating insulin-producing islets appears to protect the islets from destruction by the immune system and could greatly improve the long-term survival of islets harvested from donor pancreases and transplanted into patients with Type 1 diabetes.
Collin Weber, MD, professor of surgery in Emory University School of Medicine, developed the improved method of coating the donor islets in a jello-like combination of alginate and barium, along with collaborators at the Norwegian company, NovaMatrix-FMC. So far, in experiments with mice, the microencapsulation technique has tricked the immune system into ignoring the invasion of transplanted islets from other mice and from pigs and humans and has allowed the islets to survive unharmed.
Over the past six years, transplant researchers have made great strides in refining the "Edmonton Protocol," a procedure of harvesting islets from donated cadaver pancreases and transplanting them into patients with Type 1 diabetes. The protocol, pioneered in 2000 by a research group in Edmonton, Alberta, Canada, has allow these patients to at least temporarily forego insulin injections. Type 1 diabetes affects more than a million Americans who are unable to manufacture their own insulin because their pancreatic islets do not function properly.
The islet transplant procedure is fraught with significant challenges, however. Just as in organ transplants, patients must take toxic immunosuppressant drugs that can lead to later problems, including susceptibility to infections or cancer. Emory transplant researchers in the Emory School of Medicine and Yerkes National Primate Research Center have been international leaders in working to develop alternative, less toxic transplant drugs.
An even more worrisome problem, however, is long-term survival of the transplanted islets. They appear to function quite well for the first year or so, but gradually lose their viability, which means patients may need an additional transplant or have to resume insulin replacement. The autoimmune process that destroyed the patients' islets in the first place may cause the return of diabetes. The islets also may be exposed to high concentrations of immunosuppressant drugs in the liver, where the islets are introduced into the body.
Researchers are continuing to work on solutions, including analyzing the human response to islets, developing new drugs, or placing the transplanted islets somewhere other than the liver. A pervasive problem, however, is the shortage of donor pancreases. Only about 3,000 to 4,000 pancreases are available in the U.S. each year, and only one in three yields enough human islets for a complete transplant. The harvesting effort is very expensive, labor intensive, and unpredictable.
The answer, says Dr. Weber, may lie in islet transplants from animals, including pigs, cows, rabbits, or fish, any of which could yield large quantities of islets. These foreign islets, however, are at even greater risk for a vigorous response by the human immune system, and animal islets could contain viruses harmful to humans.
Dr. Weber and his team, including assistant professor of surgery Susan Safley, PhD, postdoctoral fellow Hong Cui, PhD, and Sean Cauffiel, in the Department of Surgery in Emory University School of Medicine, recently conducted a series of experiments in animals using microencapsulated islets. First they transplanted mouse islets from three different mouse donor types into a mouse model of diabetes. Even without any immunosuppressant drugs, the capsules remained intact and glucose levels in the mice returned to normal and remained stable for 250 days.
"We have found that all you need to do to prevent the damage and death of islets in transplants between one mouse and another," says Dr. Weber, "is to prevent the islets from coming into contact with blood vessels or organs. You don't need any medications whatsoever. We have documented this in thr ee different donor mouse types, transplanted into the toughest mouse model of childhood diabetes."
The researchers took their experiment a step further and transplanted encapsulated pig islets and human islets into the diabetic mouse model – an even greater challenge because of the unrelated donor-recipient combination. They used very limited doses of immunosuppressant drugs and achieved islet function for over one year with the pig islets and over 450 days with the human islets, with no evidence of interaction of host cells with the encapsulated islets. They are continuing to test encapsulated islets in non-human primates. They also are using a newly developed mouse model lacking an immune system to test human cell responses to encapsulated islets from humans, pigs, and fish.
Dr. Weber and his colleagues are considering other possible uses for their encapsulation technology. "Once you know that in an allograft (same species transplant) no medications are required, your eyes open to the possibility of coating all kinds of cells," he says. "For instance, erythropoietin-secreting cells to treat anemia patients on dialysis, interferon alpha for advanced carcinoma, growth hormone for dwarfism, or other conditions that require slow-release substances."
"Our laboratory has been working to improve microencapsulation for 20 years," says Dr. Weber. "We have now shown that these capsules are remarkably durable, resilient, and suitable for transplantation of donor cells within and among species. We are hopeful that this will help us make significant process in islet transplantation and delivery of other substances to humans."